Apolipoprotein E (apoE) is important in the metabolism of lipoproteins. In humans there are 3 common forms of apoE; apoE-2, apoE-3, and apoE-4. ApoE levels, apoE phenotypes, and the metabolism of apoE forms were studied. Elevated apoE concentrations were found in all groups of hyperlipidemic subjects. Previous reports of an association of apoE-2 with type III hyperlipoproteinemia (HLP) were confirmed and, in addition, apoE-4 was clearly associated with type V HLP. A new variant of apoE, apoE-Bethesda, associated with type III HLP was also discovered. ApoE kinetic studies were performed in normal and type III HLP subjects. The elevated apoE levels in type III subjects were due to both decreased catabolism and increased production. In normal subjects apoE-4 had a shorter residence time than apoR-3, and this unexpected finding suggests that apoE had another function in addition to regulating lipoprotein remnant catabolism. These results indicate that both apoE-2 and apoE-4 are associated with hyperlipidemic states, that apoE-2 and apoE-4 are metabolically distinct from apoE-3, and that additional information about apoE metabolism may be gained by screening for apoE variants and studying the metabolism of apoE in unusual forms of dyslipidemia.